Decentralised Procedure Public Assessment Report Sultiam

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Decentralised Procedure Public Assessment Report Sultiam Decentralised Procedure Public Assessment Report Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten Sultiame DE/H/4348/001-003/DC Applicant: neuraxpharm Arzneimittel GmbH, Germany Reference Member State DE TABLE OF CONTENTS I. INTRODUCTION ....................................................................................................................... 4 II. EXECUTIVE SUMMARY ..................................................................................................... 4 II.1 Problem statement ................................................................................................................... 4 II.2 About the product ................................................................................................................... 4 II.3 General comments on the submitted dossier ........................................................................ 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................. 5 III.1 Quality aspects ......................................................................................................................... 5 III.2 Non-clinical aspects ................................................................................................................. 6 III.3 Clinical aspects ........................................................................................................................ 6 IV. BENEFIT RISK ASSESSMENT ......................................................................................... 13 Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 2/13 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten product(s) in the RMS Name of the drug substance (INN Sultiame name): Pharmaco-therapeutic group N03AX03 (ATC Code): Pharmaceutical form(s) and Film-coated tablet; 50 / 100 / 200 mg strength(s): Reference Number(s) for the DE/H/4348/001-003/DC Decentralised Procedure Reference Member State: DE Member States concerned: LU withdrawn Applicant (name and address) neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Str. 23 40764 Langenfeld Germany neuraxpharm Arzneimittel GmbH Names and addresses of all proposed Elisabeth-Selbert-Str. 23 manufacturer(s) responsible for 40764 Langenfeld batch release in the EEA Germany Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 3/13 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for “Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten”, with the following indication: The medicinal product is used for the alternative treatment for Rolandic epilepsy when the treatment with other anti-epileptics has not produced the desired effect. Note: The treatment with Sultiame should only be performed by neuropaediatricians with experience in the treatment of epilepsy. The efficacy and safety of Sultiame for the above therapeutic indication have not been verified in controlled studies. Before starting a treatment with Sultiame careful differential diagnosis is required to distinguish the particular case from other forms of epilepsy in childhood. Rolandic epilepsy has a high spontaneous remission rate and in most cases a good outcome and a good prognosis - even without medication. is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Sultiame is a cyclic sulphonamide derivative. The structure of sultiame is distinct from that of other anticonvulsants. It has a carbonic anhydrase (CA) inhibitory effect which is used therapeutically as an antiepileptic drug. The exact mechanism of action of sultiame is not known. CAIs can reduce seizures through perturbation of the CO2 equilibrium and/or the inhibition of ion channels. Thus, sultiame may also act via sodium channels. Innovator products of sultiame for oral use have been approved and are marketed in several European and non-European countries. The generally accepted indication of oral sultiame products is: Alternative therapy of Rolandic epilepsy when treatment with other antiepileptics was unsuccessful. Note: Treatment with sultiame should only be performed by a neuropaediatrician experienced in epilepsy therapy. Efficacy and safety of sultiame in the aforementioned indication has not been examined in controlled clinical studies. Before the start of therapy with sultiame, a careful differential diagnostic approach concerning other types of epilepsy in childhood is indicated. Rolandic epilepsy shows a high rate of spontaneous remission and has even without medicamentous therapy mostly favourable progress and a good prognosis. II.3 General comments on the submitted dossier This decentralised application concerns a generic version of sultiame and has been submitted according to Art. 10(1) of Dir. 2001/83/EC under the trade names “Sultiam-neuraxpharm 50 / 200 mg Filmtabletten” and according to Art. 10(3) of Dir. 2001/83/EC under the trade name “Sultiam-neuraxpharm 100 mg Filmtabletten”. The originator product is “Ospolot 50 / 200 mg film- coated tablets” by Desitin Arzneimittel GmbH, Germany, registered since 3rd July1998. Hence, data protection has expired and generic products can be licensed. With Germany as the Reference Member State in this Decentralized Procedure, neuraxpharm Arzneimittel GmbH, Germany, has originally applied for the Marketing Authorisations for “Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten” in LU. However, the Company decided to withdraw marketing authorisation application for this procedure in LU due to economical reasons on August 8th, 2016. Sultiam-neuraxpharm 50 / 100 / 200 mg Filmtabletten, DE/H/4348/001-003/DC Public AR Page 4/13 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. The submitted bioequivalence study (No. 355B14) has been stated to have been performed in compliance with GCP. According to Eudra CT, no critical findings were reported for the inspections of the bioanalytical study site. With respect to the clinical study site an inspection performed by BfArM in 2006 revealed one or more critical findings. However no critical finding was identified during the inspection performed in 2013 by the AEMPS. The very recent inspection of this study site by BfArM (from 07 to 10 December 2015) revealed no critical and one or more major findings. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Sultiam- neuraxpharm 50 / 100 / 200 mg Filmtabletten are of sufficient quality in view of the present European regulatory requirements. The route of synthesis has been adequately described. The drug substance manufacturer uses a multi- step synthesis followed by purification steps. The structure of Sultiame has been confirmed by spectroscopic analyses. The proposed drug substance specification is acceptable. The analytical test methods have been sufficiently described. Satisfactory batch analysis data of three commercial scale batches of Sultiame drug substance have been presented. Stability studies have been performed with the drug substance. The data presented support the claimed re-test period of 24 months. Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The generic drug product and the innovator product exhibit the same qualitative and quantitative composition in terms of the active substance and the same pharmaceutical form. Bioequivalence of the two formulations has been demonstrated by an in vivo bioequivalence study of the 200 mg strength. The divisibility has been adequately demonstrated. As the Hardness of the tablets does not change over time no further testing is required. The manufacturing process has been adequately described. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on four batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed
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